Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Center for Translational Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand; Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.
Biochim Biophys Acta Gen Subj. 2023 Dec;1867(12):130486. doi: 10.1016/j.bbagen.2023.130486. Epub 2023 Oct 7.
Cholangiocarcinoma (CCA) exhibits poor response to the present chemotherapeutic agents and frequently develops drug resistance. Finding novel anticancer drugs might enhance patient outcomes. Tiliacorinine, a bisbenzylisoquinoline alkaloid from the Thai medicinal plant Tiliacora triandra, effectively induced apoptosis of human CCA cell lines and inhibited tumor growth in mice. Here, we elucidate further the molecular mechanisms underlining the cytotoxicity of tiliacorinine and its implication in overcoming gemcitabine-resistance of CCA cells.
Cytotoxicity of tiliacorinine against CCA cell lines was assessed using MTT assay. The molecular signaling was determined using Western blot analysis. Molecular docking simulations were applied to predict the binding affinity and orientation of tiliacorinine to the possible binding site(s) of the target proteins.
Tiliacorinine induced apoptotic cell death of CCA cells in a dose- and time-dependent manner. Tiliacorinine significantly suppressed the expression of anti-apoptotic proteins, Bcl-xL and XIAP; activated apoptotic machinery proteins, caspase-3, caspase-9, and PARP; and decreased the levels of pAkt and pSTAT3. EGF/EGFR activation model and molecular docking simulations revealed EGFR, Akt, and STAT3 as potent targets of tiliacorinine. Molecular docking simulations indicated a strong binding affinity of tiliacorinine to the ATP-binding pockets of EGFR, PI3K, Akt, JAK2, and SH2 domain of STAT3. Tiliacorinine could synergize with gemcitabine and restore the cytotoxicity of gemcitabine against gemcitabine-resistant CCA cells.
Tiliacorinine effectively induced apoptosis via binding and blocking the actions of EGFR, Akt, and STAT3.
Tiliacorinine is a novel multi-kinase inhibitor and possibly a potent anti-cancer agent, in cancers with high activation of EGFR.
胆管癌（CCA）对现有化疗药物反应不佳，常发生耐药。寻找新的抗癌药物可能会改善患者的预后。来自泰国药用植物三叶苦树的双苄基异喹啉生物碱Til iacorinine 可有效诱导人 CCA 细胞系凋亡并抑制小鼠肿瘤生长。在这里，我们进一步阐明了 Til iacorinine 细胞毒性的分子机制及其在克服 CCA 细胞对吉西他滨耐药性中的作用。
采用 MTT 法检测 Til iacorinine 对 CCA 细胞系的细胞毒性。采用 Western blot 分析检测分子信号转导。应用分子对接模拟预测 Til iacorinine 与靶蛋白可能结合位点的结合亲和力和取向。
Til iacorinine 呈剂量和时间依赖性诱导 CCA 细胞凋亡。Til iacorinine 显著抑制抗凋亡蛋白 Bcl-xL 和 XIAP 的表达；激活凋亡机制蛋白 caspase-3、caspase-9 和 PARP；并降低 pAkt 和 pSTAT3 的水平。EGF/EGFR 激活模型和分子对接模拟显示 EGFR、Akt 和 STAT3 是 Til iacorinine 的潜在靶点。分子对接模拟表明 Til iacorinine 与 EGFR、PI3K、Akt、JAK2 和 STAT3 的 SH2 结构域的 ATP 结合口袋具有很强的结合亲和力。Til iacorinine 可与吉西他滨协同作用，并恢复吉西他滨对吉西他滨耐药的 CCA 细胞的细胞毒性。
Til iacorinine 通过结合并阻断 EGFR、Akt 和 STAT3 的作用，有效诱导细胞凋亡。
Til iacorinine 是一种新型多激酶抑制剂，可能是一种有效的抗癌药物，适用于 EGFR 高激活的癌症。
